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Association of TGFb1 Haplotypes with Quantitative Traits in Allergic Reactions
Abstracts S171
J ALLERGY CLIN IMMUNOL VOLUME 121, NUMBER 2
654
Pre-treatment Specific IgE levels are not Useful in Predicting a Response to Omalizumab Therapy C. Martin, P. Freeman, M. Blogg; Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: Omalizumab, an anti-IgE antibody, has proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgEmediated) asthma. However analyses have shown that it is difficult to consistently predict which patients gain greatest benefit based on pretreatment baseline characteristics. METHODS: Univariate analyses were performed to assess whether pretreatment specific IgE and related variables could be identified that were predictive of omalizumab response in a 28-week randomized, placebocontrolled trial in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA (INNOVATE study). Specific IgE levels for six common perennial allergens, two mold allergens, total specific load (all eight specific IgEs) and the ratio of each specific IgE and total specific load to baseline total IgE were determined. The interaction between pre-treatment specific IgE and related variables with eight response measures based on exacerbations (five variables), QoL, FEV1 and physician’s overall assessment were examined. RESULTS: Data were available for 337 patients. Of these, 305 patients (90.5%) were sensitive to more than one allergen and the majority of patients were positive to dust mite allergens (Dermatophagoides pteronyssinus and Dermatophagoides farinae), with 154 patients (45.7%) testing positive to both. No consistent predictive effect for omalizumab response was observed for either individual specific IgEs, combinations of specific IgEs, total specific IgE or their ratios with total IgE (p > 0.05). CONCLUSIONS: Pre-treatment allergen specific IgE levels are not useful to predict a response to omalizumab. The most reliable method of identifying patients who respond to omalizumab treatment remains a physician’s assessment following an initial course of therapy. Funding: Novartis Pharmaceuticals
655
Association of TGFb1 Haplotypes with Quantitative Traits in Allergic Reactions J. Meng1, L. Rosenwasser2; 1Children’s Mercy Hospital/UMKC School of Medicine, Kansas City, MO, 2Children’s Mercy Hospital/UMKC Scool of Medicine, Kansas City, MO. RATIONALE: We have previously reported that a TGFb1 haplotype in promoter region was associated with higher risk of allergy in Caucasians and lower risk of allergy in Asians. The associations of the TGFb1 haplotypes with allergy related quantitative traits were further explored to understand the mechanism. METHODS: The plasma TGFb1, total IgE, CD23 and cell proliferation in response to antigens were measured in allergic patients and healthy subjects. Multiple regression analyses were conducted to test the association between the haplotypes and these quantitative traits. RESULTS: The haplotype TTA (rs224175, rs1800469 and rs1982072) was found to be significantly associated with increased plasma TGFb1 concentration accounting for about 7.4% of variance in plasma TGFb1 while allergy and race were considered as covariates (p 5 0.0277 < 0.05). There is no significant difference in terms of TTA related increase in TGFb1 between Asians and Caucasians. However, the Asians seem to have lower plasma TGFb1 than Caucacians (difference: 267 (6148.37)pg/ml,
p 5 0.0762). The haplotype TTA was not associated with plasma total IgE and CD23, but it was associated with lower basic level of cell proliferation in PBMC, maximum cell proliferation to tetanus, cat and grass allergens. CONCLUSIONS: TGFb1 concentration associated with haplotype TTA may be crucial in mediating allergy development. The different TGFb1 concentration may account for the difference in allergy risk between Asians and Caucasians. Funding: Children’s Mercy Hospital
656
Comparison of Allergy Skin Test Responses to Serum IgE: Observations from the ACE Study S. J. Arbes, Jr, 1, J. Wildfire1, H. Mitchell1, H. A. Sampson2, R. S. Gruchalla3; 1Rho, Inc., Chapel Hill, NC, 2Mount Sinai School of Medicine, New York, NY, 3Texas Southwestern Medical Center, Dallas, TX. RATIONALE: Atopy, the genetic propensity to develop immunoglobulin E (IgE) antibodies in response to exposure to allergen, is often assessed by allergy skin testing. METHODS: Allergy skin testing was conducted and total and specific IgE concentrations were measured in the Asthma Control Evaluation Study, a clinical trial involving 546 inner-city asthmatics aged 12-20 years. Correlations between allergen-specific wheal diameters and concentrations of total and specific IgE (log transformed) were evaluated for 5 allergens with Pearson correlation coefficients. The overall ability of the allergen-specific skin test to discriminate between individuals with and without elevated specific IgE (> 0.35 kU/L) was evaluated by calculating areas under the receiver operating characteristic (ROC) curves (a perfect test has an area of 1.0, a useless test 0.5). RESULTS: Correlation coefficients for associations between allergenspecific wheal sizes and specific IgE were 0.70 and 0.65 for the dust mites D. pteronyssinus and D. farinae, respectively, 0.70 for cat, 0.67 for German cockroach, and 0.57 for Alternaria tenius. Correlations between allergenspecific wheal sizes and total IgE were much weaker: from 0.18-0.37. Areas under the ROC curves were 0.92 for cat, 0.82 for German cockroach, 0.82 for D. pteronyssinus, 0.78 for D. farinae, and 0.77 for Alternaria tenius. The wheal size that provided the optimal tradeoff between sensitivity and specificity varied by allergen from 1 mm to 5 mm. CONCLUSION: Among this study population of inner-city asthmatics, the ability of allergen-specific skin tests to discriminate between persons with and without elevated specific IgE was very good. Funding: NIAID/NIH and NCRR/NIH
MONDAY
18.3621.0 (ImmunoCAP) and 151.96206 (Immulite) fold from Pre-IT, while placebo IgG4-a-TG levels remained essentially unchanged: 2.461.4 (ImmunoCAP) and 17.4627.1 (Immulite) fold. CONCLUSIONS: Both autoanalyzers displayed acceptable analytical performance and significant correlation of allergen-specific total IgG and IgG4 antibody levels with those detected by the reference IgG4-captureRIA. Quantitatively, however, measured IgG antibody levels varied between assays. The clinical significance of autoanalyzer quantified IgG and IgG4 anti-allergen measurements needs further assessment within the context of clinical measures of IT efficacy. Funding: Immune Tolerance Network
J ALLERGY CLIN IMMUNOL VOLUME 121, NUMBER 2
654
Pre-treatment Specific IgE levels are not Useful in Predicting a Response to Omalizumab Therapy C. Martin, P. Freeman, M. Blogg; Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: Omalizumab, an anti-IgE antibody, has proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgEmediated) asthma. However analyses have shown that it is difficult to consistently predict which patients gain greatest benefit based on pretreatment baseline characteristics. METHODS: Univariate analyses were performed to assess whether pretreatment specific IgE and related variables could be identified that were predictive of omalizumab response in a 28-week randomized, placebocontrolled trial in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA (INNOVATE study). Specific IgE levels for six common perennial allergens, two mold allergens, total specific load (all eight specific IgEs) and the ratio of each specific IgE and total specific load to baseline total IgE were determined. The interaction between pre-treatment specific IgE and related variables with eight response measures based on exacerbations (five variables), QoL, FEV1 and physician’s overall assessment were examined. RESULTS: Data were available for 337 patients. Of these, 305 patients (90.5%) were sensitive to more than one allergen and the majority of patients were positive to dust mite allergens (Dermatophagoides pteronyssinus and Dermatophagoides farinae), with 154 patients (45.7%) testing positive to both. No consistent predictive effect for omalizumab response was observed for either individual specific IgEs, combinations of specific IgEs, total specific IgE or their ratios with total IgE (p > 0.05). CONCLUSIONS: Pre-treatment allergen specific IgE levels are not useful to predict a response to omalizumab. The most reliable method of identifying patients who respond to omalizumab treatment remains a physician’s assessment following an initial course of therapy. Funding: Novartis Pharmaceuticals
655
Association of TGFb1 Haplotypes with Quantitative Traits in Allergic Reactions J. Meng1, L. Rosenwasser2; 1Children’s Mercy Hospital/UMKC School of Medicine, Kansas City, MO, 2Children’s Mercy Hospital/UMKC Scool of Medicine, Kansas City, MO. RATIONALE: We have previously reported that a TGFb1 haplotype in promoter region was associated with higher risk of allergy in Caucasians and lower risk of allergy in Asians. The associations of the TGFb1 haplotypes with allergy related quantitative traits were further explored to understand the mechanism. METHODS: The plasma TGFb1, total IgE, CD23 and cell proliferation in response to antigens were measured in allergic patients and healthy subjects. Multiple regression analyses were conducted to test the association between the haplotypes and these quantitative traits. RESULTS: The haplotype TTA (rs224175, rs1800469 and rs1982072) was found to be significantly associated with increased plasma TGFb1 concentration accounting for about 7.4% of variance in plasma TGFb1 while allergy and race were considered as covariates (p 5 0.0277 < 0.05). There is no significant difference in terms of TTA related increase in TGFb1 between Asians and Caucasians. However, the Asians seem to have lower plasma TGFb1 than Caucacians (difference: 267 (6148.37)pg/ml,
p 5 0.0762). The haplotype TTA was not associated with plasma total IgE and CD23, but it was associated with lower basic level of cell proliferation in PBMC, maximum cell proliferation to tetanus, cat and grass allergens. CONCLUSIONS: TGFb1 concentration associated with haplotype TTA may be crucial in mediating allergy development. The different TGFb1 concentration may account for the difference in allergy risk between Asians and Caucasians. Funding: Children’s Mercy Hospital
656
Comparison of Allergy Skin Test Responses to Serum IgE: Observations from the ACE Study S. J. Arbes, Jr, 1, J. Wildfire1, H. Mitchell1, H. A. Sampson2, R. S. Gruchalla3; 1Rho, Inc., Chapel Hill, NC, 2Mount Sinai School of Medicine, New York, NY, 3Texas Southwestern Medical Center, Dallas, TX. RATIONALE: Atopy, the genetic propensity to develop immunoglobulin E (IgE) antibodies in response to exposure to allergen, is often assessed by allergy skin testing. METHODS: Allergy skin testing was conducted and total and specific IgE concentrations were measured in the Asthma Control Evaluation Study, a clinical trial involving 546 inner-city asthmatics aged 12-20 years. Correlations between allergen-specific wheal diameters and concentrations of total and specific IgE (log transformed) were evaluated for 5 allergens with Pearson correlation coefficients. The overall ability of the allergen-specific skin test to discriminate between individuals with and without elevated specific IgE (> 0.35 kU/L) was evaluated by calculating areas under the receiver operating characteristic (ROC) curves (a perfect test has an area of 1.0, a useless test 0.5). RESULTS: Correlation coefficients for associations between allergenspecific wheal sizes and specific IgE were 0.70 and 0.65 for the dust mites D. pteronyssinus and D. farinae, respectively, 0.70 for cat, 0.67 for German cockroach, and 0.57 for Alternaria tenius. Correlations between allergenspecific wheal sizes and total IgE were much weaker: from 0.18-0.37. Areas under the ROC curves were 0.92 for cat, 0.82 for German cockroach, 0.82 for D. pteronyssinus, 0.78 for D. farinae, and 0.77 for Alternaria tenius. The wheal size that provided the optimal tradeoff between sensitivity and specificity varied by allergen from 1 mm to 5 mm. CONCLUSION: Among this study population of inner-city asthmatics, the ability of allergen-specific skin tests to discriminate between persons with and without elevated specific IgE was very good. Funding: NIAID/NIH and NCRR/NIH
MONDAY
18.3621.0 (ImmunoCAP) and 151.96206 (Immulite) fold from Pre-IT, while placebo IgG4-a-TG levels remained essentially unchanged: 2.461.4 (ImmunoCAP) and 17.4627.1 (Immulite) fold. CONCLUSIONS: Both autoanalyzers displayed acceptable analytical performance and significant correlation of allergen-specific total IgG and IgG4 antibody levels with those detected by the reference IgG4-captureRIA. Quantitatively, however, measured IgG antibody levels varied between assays. The clinical significance of autoanalyzer quantified IgG and IgG4 anti-allergen measurements needs further assessment within the context of clinical measures of IT efficacy. Funding: Immune Tolerance Network